The invention relates to methods for identifying compounds useful in the treatment of Alzheimer's disease (AD).
Abnormalities of the neuronal endocytic pathway (EP) are the earliest cellular manifestation of sporadic AD (SAD) yet demonstrated. Importantly, EP abnormalities distinguish SAD from certain other subtypes of AD caused by presenilin mutations.
Early endosomes are the site of internalization and initial processing of amyloid precursor protein (APP) and apolipoprotein E (ApoE). They are also a major site of both amyloid β peptide (Aβ) formation and mediate the cellular uptake of Aβ and soluble APP. Individual neuronal endosomes can be as much as 32-fold larger in volume than the normal average and the total endosome volume can be 3-fold higher in SAD brain. Because of a concurrent activation of the lysosomal system (LS), lysosomal acid hydrolases (including proteases) are targetted to early endosomes in increased amounts. These findings, coupled with evidence for the increased mobilization of regulatory proteins of endocytosis, imply a strong upregulation of the EP in Alzheimer's disease.
Greater than 90% of all AD cases are sporadic. Currently there is no suitable animal model for sporadic AD. The early appearance of EP abnormalities and the specificity of these abnomralities in SAD patients suggest that these abnormalities reflect an important pathologic mechanism relevant to the most common form of AD, particularly the β-amyloidogenesis in SAD, the mechanism of which is currently unknown. Thus, there is a need for cellular or animal models of this increased activity, both for increasing the understanding of the pathophysiology underlying AD, and for use in assaying drugs for their use in treating or preventing AD.
Despite the extensive study of AD, the pathogenetic significance of the upregulation of the EP remains unclear. Thus, there is also a long-sought need to understand the importance of increased endocytosis and lysosomal activity in AD.